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Caffeine Metabolism
Overview ]] Caffeine is known as to what a lot of people have in the morning to start off the day. Caffeine is a widely used natural stimulant found in coffee, tea, chocolate, and used as an additive in beverages (3). Some people can feel the “jitters” or a bit jumpy after drinking a cup of coffee, while some feel nothing at all. Caffeine tolerance can be the answer for one part, but genetic variability within caffeine metabolism can also be the case (1). Caffeine is mostly metabolized through the liver enzyme cytochrome P450 1A2 (CYP1A2) (1). This enzyme is encoded by the gene CYP1A2 (4). It can be located on the endoplasmic reticulum and can be induced by polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke, aflatoxin B1 (mycotoxin), acetaminophen (pain reliever) and ultimately caffeine (4). This enzyme is a monooxygenase which catalyze many reactions involved in drug metabolism, synthesis of cholesterol, steroids and other lipids (4). The formation of SNP rs762551 determines how fast one’s metabolism for caffeine (1). Caffeine Metabolites and Pathway Caffeine travels through the small intestine, where it is absorbed, then metabolized in liver cells (2). Once metabolized by the liver cells it is distributed to the body, which approximately takes 45 minutes of ingestion (2). The half-life in adults is 3-5 hours but varies when it comes to pregnant women (2). Caffeine is broken down into three different metabolites: paraxanthine, theobromine, and theophylline (2). Paraxanthine is the highest percentage of metabolite produced when caffeine is broken down; with the percentage of 84% (2). This increases lipolysis, which is the breakdown of lipids (2). Lipolysis causes elevated glycerol and free fatty acid levels in the blood plasma (2). The second most metabolite produced is theobromine with the percentage of 12%. Theobromine dilates blood vessels and increases urine volume. The last metabolite produced at 4% is theophylline (2). This metabolite relaxes smooth muscles in the brochi (2). Within this pathway, caffeine has an indirect effect of the regulation with cAMP-dependent protein kinases (2). These protein kinases are responsible for the regulation of glycogen, sugar, lipid metabolism, as well as the release of hormones such as epinephrine (2). Caffeine causes this indirect affect by inhibiting the enzyme phosphodiesterase (2). Phosphodiesterase is the enzyme that has the function of degrading cyclic AMP (cAMP) (2). Since phosophodiesterase isn’t able to fulfill its function, there is an increasing amount of cAMP (2). 23andMe The website 23andMe shows the results of John Burke, who is heterozygous (AC) for caffeine metabolism. Since he is heterozygous this indicates that he has the dominant phenotype of slow caffeine metabolizer: which causes an increased risk to a heart attack. This issue of not being able to fully break down caffeine causes a higher risk of heart disease. There is a higher risk due to the fact that caffeine is structurally similar to the molecule adenosine. Adenosine when injected intravenously can cause transient heart block. On the results page it contains a table that shows the genotype and the genetic result due to that genotype. It also shows the other possible combinations of alleles and what their phenotypes would show. If a subject is shown to be homozygous recessive it indicates that that person would have a genotype of AA. To have this genotype that would mean that the subject would have a fast metabolism to caffeine. To have the homozygous dominant genotype it would show CC, resulting in the same phenotype as our subject, John Burke. Another interesting utilization of this page shows the “Applicable Ethnicities” which means where this gene derives from in his ancestry. For the subject, John Burke, his Applicable Ethnicity is European (1). Resources 1. John Burke. 23andMe. 2007-2014. https://www.23andme.com/you/journal/pre_caffeine_metabolism/overview/ 2. Metabolism of Caffeine. Effects of Caffeine. http://udel.edu/~danikoll/metabolism.html 3. Caffeine Pathway, Pharmacokinetics. PharmGKB. http://www.pharmgkb.org/pathway/PA165884757 4. CYP1A2. Wikipedia. 2011. http://en.wikipedia.org/wiki/CYP1A2